Gastro-retentive sustained-release oral dosage form of a bile acid sequestrant

Abstract

Disclosed herein are novel compositions and methods for controlling the release of bile acid sequestrant to the stomach in order to treat or prevent upper GI tract disorders or disorders of the throat. The methods generally include administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising at least one bile acid sequestrant dispersed in a polymeric matrix. The bite acid sequestrant composition may be administered alone or in combination with at least one proton pump inhibitor, and optionally one or more agents chosen from antacids, histamine H 2 -receptor antagonists, γ-aminobutyric acid-β (GABA-B) agonists, prodrugs of GABA-B agonists, acid pump antagonists, protease inhibitors and GC-C agonists.

We claim: 
     
         1 . A gastro-retentive, oral dosage form for sustained release of a bile acid sequestrant to the stomach for the treatment of a disease of the upper gastrointestinal tract or the throat, wherein said dosage form comprises a bile acid sequestrant dispersed in a polymeric matrix, wherein the polymeric matrix comprises one or more hydrophilic polymers such dial, upon imbibition of gastric fluid, said dosage form swells to a size sufficient to promote gastric retention for a period of time of 3 hours or longer and wherein the bile acid sequestrant is released from the dosage form through erosion of the polymeric matrix over an extended period of time of at least 3 hours. 
     
     
         2 . The gastro-retentive, oral dosage form of  claim 1  which is in the form of a tablet. 
     
     
         3 . The gastro-retentive, oral dosage form of  claim 1 , wherein the bile acid sequestrant is selected from cholestyramine, colesevelam, colesevelam hydrochloride, colestipol or selevamer. 
     
     
         4 - 11 . (canceled) 
     
     
         12 . The gastro-retentive, oral dosage form of  claim 1 , wherein the polymeric matrix erodes during a period of drug release, wherein the period of drug release is at least 6 hours. 
     
     
         13 - 17 . (canceled) 
     
     
         18 . The gastro-retentive, oral dosage form of  claim 1 , wherein the rate of drug release measured in vitro, in acetate buffer at pH 4.5, using a USP Type II (paddle) apparatus with the tablets placed in sinkers is such that not more than 40% percent of the drug has been released from the dosage from after 4 hours. 
     
     
         19 - 31 . (canceled) 
     
     
         32 . The gastro-retentive, oral dosage form of  claim 1 , wherein the hydrophilic polymeric matrix comprises two hydrophilic polymers. 
     
     
         33 . The gastro-retentive, oral dosage form of  claim 32 , wherein the first hydrophilic polymer is a poly(alkylene)oxide. 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . The gastro-retentive, oral dosage form of  claim 33 , wherein the poly(alkylene)oxide is present in an amount ranging from 40 weight percent ratio to 75 weight percent ratio. 
     
     
         37 - 42 . (canceled) 
     
     
         43 . The gastro-retentive, oral dosage form of  claim 1  wherein at least one of the one or more hydrophilic polymers is a polyethylene oxide having a molecular weight of about 2,000,000 to 4,000,000 Daltons. 
     
     
         44 . The gastro-retentive, oral dosage form of  claim 43 , wherein a second hydrophilic polymer of the one or more hydrophilic polymers is used as a binder and is selected from povidone, starch, hydroxypropylcellulose, and hydroxypropylmethylcellulose. 
     
     
         45 . The gusto-retentive, oral dosage form of  claim 1 , wherein the dose of the bile acid sequestrant is between 100 mg and 750 mg. 
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . The gastro-retentive, oral dosage form of  claim 1  further comprising a coating, wherein the level of coating is between 5% and 7.5% (weight: weight) of the total tablet weight. 
     
     
         49 . The gastro-retentive, oral dosage form of  claim 1  further comprising a coating, wherein the coating comprises a microcrystalline cellulose and an acetylated glyceride. 
     
     
         50 - 57 . (canceled) 
     
     
         58 . The gastro-retentive oral dosage form of  claim 1 , wherein said gastro-retentive oral dosage form swells to a size that is at least 130% of the original size within 2 hours. 
     
     
         59 . (canceled) 
     
     
         60 . The gastro-retentive oral dosage form of  claim 1 , wherein said gastro-retentive oral dosage form comprises two polymers, wherein both polymers are swelling and hydrophilic erodible polymers. 
     
     
         61 . (canceled) 
     
     
         62 . The gastro-retentive oral dosage form of  claim 1 , wherein said gastro-retentive oral dosage form comprises two polymers, wherein one of the polymers is a swelling and hydrophilic erodible polymer and the other polymer is a swelling and non-hydrophilic non-erodible polymer. 
     
     
         63 . (canceled) 
     
     
         64 . (canceled) 
     
     
         65 . The gastro-retentive oral dosage form of  claim 1 , wherein said gastro-retentive oral dosage form comprises two polymers, wherein one of the polymers is a swelling and hydrophilic erodible polymer and the other polymer is a non-swelling and hydrophilic erodible polymer. 
     
     
         66 . (canceled) 
     
     
         67 . (canceled) 
     
     
         68 . A pharmaceutical composition comprising the gastro-retentive oral dosage form of  claim 1  and an additional therapeutic agent. 
     
     
         69 - 76 . (canceled) 
     
     
         77 . A method of administering a therapeutically effective amount of a daily dose of about 100 mg to about 4000 mg of a bile acid sequestrant to a subject in need thereof, comprising administering a subject in need thereof, the gastric-retentive oral dosage form of  claim 1 , wherein the subject is in the fed state. 
     
     
         78 . A method of treating a subject suffering from a disease selected from heartburn, indigestion, dyspepsia, erosive esophagitis, peptic ulcer, gastric ulcer, esophageal ulcers, esophagitis, laryngitis, pharyngitis, coarse voice, gastroesophageal reflux disease (GERD), Barrett's esophagus, gastric cancer, esophageal cancer (e.g., adenocarcinoma), gastritis and GERD-related pulmonary dysfunction, comprising administering to the subject a total daily dose of about 100 mg to about 4000 mg of a bile acid sequestrant in the form of the gastric retentive oral dosage form of  claim 1 . 
     
     
         79 - 88 . (canceled)